A volumetric comparison of the insular cortex and its subregions in primates.

The neuronal composition of the insula in primates displays a gradient, transitioning from granular neocortex in the posterior-dorsal insula to agranular neocortex in the anterior-ventral insula with an intermediate zone of dysgranularity. Additionally, apes and humans exhibit a distinctive subdomain in the agranular insula, the frontoinsular cortex (FI), defined by the presence of clusters of von Economo neurons (VENs). Studies in humans indicate that the ventral anterior insula, including agranular insular cortex and FI, is involved in social awareness, and that the posterodorsal insula, including granular and dysgranular cortices, produces an internal representation of the body's homeostatic state.We examined the volumes of these cytoarchitectural areas of insular cortex in 30 primate species, including the volume of FI in apes and humans. Results indicate that the whole insula scales hyperallometrically (exponent=1.13) relative to total brain mass, and the agranular insula (including FI) scales against total brain mass with even greater positive allometry (exponent=1.23), providing a potential neural basis for enhancement of social cognition in association with increased brain size. The relative volumes of the subdivisions of the insular cortex, after controlling for total brain volume, are not correlated with species typical social group size. Although its size is predicted by primate-wide allometric scaling patterns, we found that the absolute volume of the left and right agranular insula and left FI are among the most differentially expanded of the human cerebral cortex compared to our closest living relative, the chimpanzee.

Increased affective bias revealed using experimental graded heat stimuli in young depressed adults: evidence of "emotional allodynia".

OBJECTIVE: To examine the hypothesis that young adults with major depressive disorder (MDD) would show increased affective bias to painful and nonpainful experimental heat stimuli, as evidenced by an increased responsiveness to warm and hot temperatures. Pain and depression often occur together. Pain is both a sensation and an affective experience. Similarly, depression is associated frequently with somatic symptoms as well as emotional dysphoria. Existing evidence indicates that MDD may be associated with altered pain processing. However, the extent to which alterations in experimentally controlled heat pain sensations are related to increased affective bias in MDD is unknown. METHOD: Graded nonnoxious and noxious heat stimuli were delivered randomly with a thermode applied to the volar surface of the left arm of 15 unmedicated subjects with current MDD and 15 age- and gender-matched healthy comparison subjects. MDD and non-MDD subjects rated the intensity and unpleasantness of all stimuli. RESULTS: Two main results were observed. First, MDD relative to non-MDD subjects showed decreased heat pain thresholds. Second, a significantly increased affective bias (unpleasantness/intensity) was observed in subjects with MDD, particularly over the range of nonnoxious heat stimuli. This bias was independent of the change in sensory pain thresholds. CONCLUSION: These findings represent corroborative evidence of abnormal affective heat pain processing in young adults with MDD, and suggest that MDD is associated with "emotional allodynia," a qualitatively altered negative emotional response to normally nonaversive thermal stimuli.

Central neural substrates involved in temperature discrimination, thermal pain, thermal comfort, and thermoregulatory behavior.

A phylogenetically novel pathway that emerged with primate encephalization is described, which conveys high-fidelity cutaneous thermosensory activity in "labeled lines" to a somatotopic map in the dorsal posterior insular cortex. It originates in lamina I of the superficial dorsal horn and ascends by way of the lateral spinothalamic tract and a distinct region in posterolateral thalamus. It evolved from the homeostatic sensory activity that represents the physiologic (interoceptive) condition of the body and drives the central autonomic network, which underlies all affective feelings from the body. Accordingly, human discriminative thermal sensations are accompanied by thermally motivated behaviors and thermal feelings of comfort or discomfort (unless neutral), which evidence suggests are associated with activity in the insular, cingulate, and orbitofrontal cortices, respectively. Yet, the substrates for thermoregulatory behavior have not been established, and several strong candidates (including the hypothalamus and the bed nucleus of the stria terminalis) are discussed. Finally, the neural underpinnings for relationships between thermal affect and social feelings (warm-positive/cold-negative) are addressed, including the association of hyperthermia with clinical depression.

Gamma Knife surgery targeting the centromedian nucleus of the thalamus for the palliative management of thalamic pain: durable response in stroke-induced thalamic pain syndrome.

The authors report the neuroimaging features, treatment planning, and outcome in a case of radiosurgical thalamotomy targeting the centromedian nucleus (CMN) for stroke-induced thalamic pain. A 79-year-old man, with embolic occlusion of the left middle cerebral artery and large hemispheric infarction involving the thalamus, suffered a right hemiplegia and expressive aphasia. One year poststroke, severe right-sided facial, scalp, arm, and trunk pain developed and was exacerbated by any tactile contact. Medical treatment had failed. Medical illness, including mandatory anticoagulation therapy for atrial fibrillation, precluded surgical procedures. Minimally invasive radiosurgery was offered as an alternative. Magnetic resonance imaging and computed tomography were used to localize the left CMN. A single shot of 140 Gy was delivered to the 100% isodose line by using the 4-mm collimator helmet. The patient was evaluated at regular intervals. By 12 weeks posttreatment, he had significant improvements in pain control and his ability to tolerate physical contact during activities of daily living. Magnetic resonance imaging demonstrated baseline encephalomalacia from his prior stroke, and signal changes in the left CMN consistent with gamma irradiation-based thalamotomy. Currently, nearly 7 years after radiosurgery, he continues to enjoy a marked reduction in pain without the need of analgesic medications. Thalamic pain syndrome is generally refractory to conventional treatment. Neurosurgical interventions provide modest benefit and carry associated risks of invasive surgery and anesthesia. The CMN is readily localized with neuroimaging and is an approximate target to reduce the suffering aspect of pain. In this case, radiosurgery was a safe and effective treatment, providing durable symptom control and improved quality of life.

Interoception, homeostatic emotions and sympathovagal balance.

We briefly review the evidence for distinct neuroanatomical substrates that underlie interoception in humans, and we explain how they substantialize feelings from the body (in the insular cortex) that are conjoined with homeostatic motivations that guide adaptive behaviours (in the cingulate cortex). This hierarchical sensorimotor architecture coincides with the limbic cortical architecture that underlies emotions, and thus we regard interoceptive feelings and their conjoint motivations as homeostatic emotions We describe how bivalent feelings, emotions and sympathovagal balance can be organized and regulated efficiently in the bicameral forebrain as asymmetric positive/negative, approach/avoidance and parasympathetic/sympathetic components. We provide original evidence supporting this organization from studies of cardiorespiratory vagal activity in monkeys and functional imaging studies in healthy humans showing activation modulated by paced breathing and passively viewed emotional images. The neuroanatomical architecture of interoception provides deep insight into the functional organization of all emotional feelings and behaviours in humans.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'.

Central neuropathic pain in MS is due to distinct thoracic spinal cord lesions.

OBJECTIVE: To determine a neuro-anatomic cause for central neuropathic pain (CNP) observed in multiple sclerosis (MS) patients. METHODS: Parallel clinical and neuro-anatomical studies were performed. A clinical investigation of consecutively acquired MS patients with and without CNP (i.e. cold allodynia or deep hyperesthesia) within a single MS center was pursued. A multivariate logistic regression model was used to assess the relationship between an upper central thoracic spinal cord focus to central pain complaints. To identify the hypothesized autonomic interneurons with bilateral descending projections to lumbosacral sensory neurons, retrograde single- and double-labeling experiments with CTb and fluorescent tracers were performed in three animal species (i.e. rat, cat, and monkey). RESULTS: Clinical data were available in MS patients with (n = 32; F:23; median age: 34.6 years (interquartile range [IQR]: 27.4-45.5)) and without (n = 30; F:22; median age: 36.6 years [IQR: 31.6-47.1]) CNP. The value of a central focus between T1-T6 in relation to CNP demonstrated a sensitivity of 96.9% (95% confidence interval [CI]: 83.8-99.9) and specificity of 83.3% (95% CI: 65.3-94.4). A significant relationship between CNP and a centrally located focus within the thoracic spine was also observed (odds ratio [OR]: 155.0 [95% CI lower limit: 16.0]; P < 0.0001, two-tailed Fisher exact test). In all animal models, neurons with bilateral descending projections to the lumbosacral superficial dorsal horn were concentrated in the autonomic intermediomedial nucleus surrounding the mid-thoracic central canal. INTERPRETATION: Our observations provide the first evidence for the etiology of CNP. These data may assist with the development of refined symptomatic therapies and allow for insights into unique pain syndromes observed in other demyelinating subtypes.

The effects of slow breathing on affective responses to pain stimuli: an experimental study.

This study examined whether breathing rate affected self-reported pain and emotion following thermal pain stimuli in women with fibromyalgia syndrome (FM: n=27) or age-matched healthy control women (HC: n=25). FM and HC were exposed to low and moderate thermal pain pulses during paced breathing at their normal rate and one-half their normal rate. Thermal pain pulses were presented in four blocks of four trials. Each block included exposure to both mild and moderate pain trials, and periods of both normal and slow paced breathing. Pain intensity and unpleasantness were recorded immediately following each pain trial, and positive and negative affect were assessed at the end of each block of trials. Compared to normal breathing, slow breathing reduced ratings of pain intensity and unpleasantness, particularly for moderately versus mildly painful thermal stimuli. The effects of slow breathing on pain ratings were less reliable for FM patients than for HCs. Slow versus normal breathing decreased negative affect ratings following thermal pain pulses for both groups, and increased positive affect reports, but only for healthy controls with high trait negative affect. Participants who reported higher levels of trait positive affect prior to the experiment showed greater decreases in negative affect as a result of slow versus normal breathing. These experimental findings provide support for prior reports on the benefits of yogic breathing and mindful Zen meditation for pain and depressed affect. However, chronic pain patients may require more guidance to obtain therapeutic benefit from reduced breathing rates.

The relationship between amygdala activation and passive exposure time to an aversive cue during a continuous performance task.

The allocation of attention modulates negative emotional processing in the amygdala. However, the role of passive exposure time to emotional signals in the modulation of amygdala activity during active task performance has not been examined. In two functional Magnetic Resonance Imaging (fMRI) experiments conducted in two different groups of healthy human subjects, we examined activation in the amygdala due to cued anticipation of painful stimuli while subjects performed a simple continuous performance task (CPT) with either a fixed or a parametrically varied trial duration. In the first experiment (N = 16), engagement in the CPT during a task with fixed trial duration produced the expected attenuation of amygdala activation, but close analysis suggested that the attenuation occurred during the period of active engagement in CPT, and that amygdala activity increased proportionately during the remainder of each trial, when subjects were passively exposed to the pain cue. In the second experiment (N = 12), the duration of each trial was parametrically varied, and we found that amygdala activation was linearly related to the time of passive exposure to the anticipatory cue. We suggest that amygdala activation during negative anticipatory processing depends directly on the passive exposure time to the negative cue.

Association of major depressive disorder with altered functional brain response during anticipation and processing of heat pain.

CONTEXT: Chronic pain and depression are highly comorbid conditions, yet little is known about the neurobiological basis of pain processing in major depressive disorder (MDD). OBJECTIVE: To examine the neural substrates underlying anticipation and processing of heat pain in a group of unmedicated young adults with current MDD. DESIGN: Functional magnetic resonance neuroimaging data were collected during an event-related factorial experimental pain paradigm. Painful and nonpainful heat stimuli were applied to the left volar forearm while different color shapes explicitly signaled the intensity of the upcoming stimulus. SETTING: University brain imaging center. Patients Fifteen (12 female) young adults with current MDD and 15 (10 female) healthy subjects with no history of MDD were recruited and matched for age and level of education. The Structured Clinical Interview for DSM-IV was administered to all participants by a board-certified psychiatrist. Main Outcome Measure Between-group differences in blood oxygen level-dependent functional magnetic resonance neuroimaging signal change to anticipation and processing of painful vs nonpainful temperature stimuli. RESULTS: Subjects with MDD compared with healthy controls showed (1) increased activation in the right anterior insular region, dorsal anterior cingulate, and right amygdala during anticipation of painful relative to nonpainful stimuli, (2) increased activation in the right amygdala and decreased activation in periaqueductal gray matter and the rostral anterior cingulate and prefrontal cortices during painful stimulation relative to nonpainful stimulation, and (3) greater activation in the right amygdala during anticipation of pain, which was associated with greater levels of perceived helplessness. CONCLUSIONS: These findings suggest that increased emotional reactivity during the anticipation of heat pain may lead to an impaired ability to modulate pain experience in MDD. Future studies should examine the degree to which altered functional brain response during anticipatory processing affects the ability to modulate negative affective states in MDD, which is a core characteristic of this disorder.